Introducing engineered nanoparticles (NPs) into a biofluid such as blood plasma leads to the formation of a selective and reproducible protein corona at the particle–protein interface, driven by the ...relationship between protein–NP affinity and protein abundance. This enables scalable systems that leverage protein–nano interactions to overcome current limitations of deep plasma proteomics in large cohorts. Here the importance of the protein to NP‐surface ratio (P/NP) is demonstrated and protein corona formation dynamics are modeled, which determine the competition between proteins for binding. Tuning the P/NP ratio significantly modulates the protein corona composition, enhancing depth and precision of a fully automated NP‐based deep proteomic workflow (Proteograph). By increasing the binding competition on engineered NPs, 1.2–1.7× more proteins with 1% false discovery rate are identified on the surface of each NP, and up to 3× more proteins compared to a standard plasma proteomics workflow. Moreover, the data suggest P/NP plays a significant role in determining the in vivo fate of nanomaterials in biomedical applications. Together, the study showcases the importance of P/NP as a key design element for biomaterials and nanomedicine in vivo and as a powerful tuning strategy for accurate, large‐scale NP‐based deep proteomic studies.
By increasing competition at the nano–bio interface, protein corona diversity and detection of low‐abundance proteins such as cytokines and chemokines are significantly improved. Quantitative mass spectrometry (MS) data captures corona dynamics for 3000 individual proteins and provides a crucial resource for in‐depth modeling of nano–bio interactions and the Vroman effect for in vitro and in vivo applications of nanomaterials.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aging is intimately linked to system‐wide metabolic changes that can be captured in blood. Understanding biological processes of aging in humans could help maintain a healthy aging trajectory and ...promote longevity. We performed untargeted plasma metabolomics quantifying 770 metabolites on a cross‐sectional cohort of 268 healthy individuals including 125 twin pairs covering human lifespan (from 6 months to 82 years). Unsupervised clustering of metabolic profiles revealed 6 main aging trajectories throughout life that were associated with key metabolic pathways such as progestin steroids, xanthine metabolism, and long‐chain fatty acids. A random forest (RF) model was successful to predict age in adult subjects (≥16 years) using 52 metabolites (R2 = .97). Another RF model selected 54 metabolites to classify pediatric and adult participants (out‐of‐bag error = 8.58%). These RF models in combination with correlation network analysis were used to explore biological processes of healthy aging. The models highlighted established metabolites, like steroids, amino acids, and free fatty acids as well as novel metabolites and pathways. Finally, we show that metabolic profiles of twins become more dissimilar with age which provides insights into nongenetic age‐related variability in metabolic profiles in response to environmental exposure.
Global profiling of plasma metabolites in a cohort of twins by liquid chromatography coupled with mass spectrometry and investigation of the biological processes involved in healthy aging.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand ...the earliest stages of T2D better, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host-microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Duchenne Muscular Dystrophy (DMD) is a fatal X‐linked genetic disorder. In DMD, the absence of the dystrophin protein causes decreased sarcolemmal integrity resulting in progressive replacement of ...muscle with fibrofatty tissue. The effects of lacking dystrophin on muscle and systemic metabolism are still unclear. Therefore, to determine the impact of the absence of dystrophin on metabolism, we investigated the metabolic and lipid profile at two different, well‐defined stages of muscle damage and stabilization in mdx mice. We measured NMR‐detectable metabolite and lipid profiles in the serum and muscles of mdx mice at 6 and 24 weeks of age. Metabolites were determined in muscle in vivo using 1H MRI/MRS, in isolated muscles using 1H‐HR‐MAS NMR, and in serum using high resolution 1H/13C NMR. Dystrophic mice were found to have a unique lipid saturation profile compared with control mice, revealing an age‐related metabolic change. In the 6‐week‐old mdx mice, serum lipids were increased and the degree of lipid saturation changed between 6 and 24 weeks. The serum taurine‐creatine ratio increased over the life span of mdx, but not in control mice. Furthermore, the saturation index of lipids increased in the serum but decreased in the tissue over time. Finally, we demonstrated associations between MRI‐T2, a strong indicator of inflammation/edema, with tissue and serum lipid profiles. These results indicate the complex temporal changes of metabolites in the tissue and serum during repetitive bouts of muscle damage and regeneration that occur in dystrophic muscle.
This is the first study to investigate metabolite and lipid profiles at two different stages of disease progression in mdx mice using NMR of serum, HR‐MAS NMR in tissues, and in vivo MRI T2. Lipid saturation and metabolite alterations suggest a complex, temporal interplay between metabolism in the tissue and serum at different stages of disease in mdx mice.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Motivation
Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the ...course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.
Results
We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.
Availability and implementation
Datasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.
Supplementary information
Supplementary data are available at Bioinformatics online.
Compound identification is a major bottleneck in metabolomics studies. In nuclear magnetic resonance (NMR) investigations, resonance overlap often hinders unambiguous database matching or de novo ...compound identification. In liquid chromatography-mass spectrometry (LC-MS), discriminating between biological signals and background artifacts and reliable determination of molecular formulae are not always straightforward. We have designed and implemented several NMR and LC-MS approaches that utilize
13
C, either enriched or at natural abundance, in metabolomics applications. For LC-MS applications, we describe a technique called isotopic ratio outlier analysis (IROA), which utilizes samples that are isotopically labeled with 5% (test) and 95% (control)
13
C. This labeling strategy leads to characteristic isotopic patterns that allow the differentiation of biological signals from artifacts and yield the exact number of carbons, significantly reducing possible molecular formulae. The relative abundance between the test and control samples for every IROA feature can be determined simply by integrating the peaks that arise from the 5 and 95% channels. For NMR applications, we describe two
13
C-based approaches. For samples at natural abundance, we have developed a workflow to obtain
13
C–
13
C and
13
C–
1
H statistical correlations using 1D
13
C and
1
H NMR spectra. For samples that can be isotopically labeled, we describe another NMR approach to obtain direct
13
C–
13
C spectroscopic correlations. These methods both provide extensive information about the carbon framework of compounds in the mixture for either database matching or
de novo
compound identification. We also discuss strategies in which
13
C NMR can be used to identify unknown compounds from IROA experiments. By combining technologies with the same samples, we can identify important biomarkers and corresponding metabolites of interest.
Dietary fibers act through the microbiome to improve cardiovascular health and prevent metabolic disorders and cancer. To understand the health benefits of dietary fiber supplementation, we ...investigated two popular purified fibers, arabinoxylan (AX) and long-chain inulin (LCI), and a mixture of five fibers. We present multiomic signatures of metabolomics, lipidomics, proteomics, metagenomics, a cytokine panel, and clinical measurements on healthy and insulin-resistant participants. Each fiber is associated with fiber-dependent biochemical and microbial responses. AX consumption associates with a significant reduction in LDL and an increase in bile acids, contributing to its observed cholesterol reduction. LCI is associated with an increase in Bifidobacterium. However, at the highest LCI dose, there is increased inflammation and elevation in the liver enzyme alanine aminotransferase. This study yields insights into the effects of fiber supplementation and the mechanisms behind fiber-induced cholesterol reduction, and it shows effects of individual, purified fibers on the microbiome.
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•Cross-over clinical trial examines how highly purified fibers select a specific microbiome•Arabinoxylan decreases cholesterol in part through increased bile acid synthesis•Cholesterol responders ate more protein and had higher levels of feruloyl esterase•High doses of inulin cause inflammation and elevation of alanine aminotransferase (ALT)
Lancaster et al. directly test the effects of two highly purified fibers on extensive clinical and biochemical profiles. They found that arabinoxylan, a common fiber of Metamucil, reduced cholesterol through bile acid production, whereas inulin, a common fiber of many vegetables, had no effect, although high doses caused inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Muscle damage is currently assessed through methods such as muscle biopsy, serum biomarkers, functional testing, and imaging procedures, each with its own inherent limitations, and a pressing need ...for a safe, repeatable, inexpensive, and noninvasive modality to assess the state of muscle health remains. Our aim was to develop and assess near-infrared (NIR) optical imaging as a novel noninvasive method of detecting and quantifying muscle damage. An immobilization–reambulation model was used for inducing muscle damage and recovery in the lower hindlimbs in mice. Confirmation of muscle damage was obtained using in vivo indocyanine green–enhanced NIR optical imaging, magnetic resonance imaging, and ex vivo tissue analysis. The soleus of the immobilized–reambulated hindlimb was found to have a greater amount of muscle damage compared to that in the contralateral nonimmobilized limb, confirmed by in vivo indocyanine green–enhanced NIR optical imaging (3.86-fold increase in radiant efficiency), magnetic resonance imaging (1.41-fold increase in T2 ), and an ex vivo spectrophotometric assay of indocyanine green uptake (1.87-fold increase in normalized absorbance). Contrast-enhanced NIR optical imaging provides a safe, sensitive, rapid, and noninvasive screening method that can be used for imaging and quantifying muscle damage and recovery in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Reactive oxygen species (ROS) play critical roles in metabolism and disease, yet a comprehensive analysis of the cellular response to oxidative stress is lacking. To systematically identify ...regulators of oxidative stress, we conducted genome-wide Cas9/CRISPR and shRNA screens. This revealed a detailed picture of diverse pathways that control oxidative stress response, ranging from the TCA cycle and DNA repair machineries to iron transport, trafficking, and metabolism. Paradoxically, disrupting the pentose phosphate pathway (PPP) at the level of phosphogluconate dehydrogenase (PGD) protects cells against ROS. This dramatically alters metabolites in the PPP, consistent with rewiring of upper glycolysis to promote antioxidant production. In addition, disruption of peroxisomal import unexpectedly increases resistance to oxidative stress by altering the localization of catalase. Together, these studies provide insights into the roles of peroxisomal matrix import and the PPP in redox biology and represent a rich resource for understanding the cellular response to oxidative stress.
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•Genome-wide shRNA and CRISPR screens identify modifiers of oxidative stress sensitivity•PEX gene perturbation protects cells via catalase redistribution•Disruption of the pentose phosphate pathway protects cells by metabolic rewiring
Despite its importance in metabolism and disease, a comprehensive analysis of the cellular response to oxidative stress is lacking. Here, Dubreuil et al. use genome-wide screens to identify cellular regulators of oxidative stress. They investigate paradoxical mechanisms by which disruption of the pentose phosphate and peroxisomal import pathways protect cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Assessment of muscle pathology is a key outcome measure to measure the success of
clinical trials studying muscular dystrophies; however, few robust minimally invasive
measures exist. Indocyanine ...green (ICG)-enhanced near-infrared (NIR) optical imaging
offers an objective, minimally invasive, and longitudinal modality that can quantify
pathology within muscle by imaging uptake of ICG into the damaged muscles. Dystrophic mice
lacking dystrophin (mdx) or gamma-sarcoglycan (Sgcg−/−) were compared to
control mice by NIR optical imaging and magnetic resonance imaging (MRI). We determined
that optical imaging could be used to differentiate control and dystrophic mice, visualize
eccentric muscle induced by downhill treadmill running, and restore the membrane integrity
in Sgcg−/− mice following adeno-associated virus (AAV) delivery of recombinant
human SGCG (desAAV8hSGCG). We conclude that NIR optical imaging is comparable to MRI and
can be used to detect muscle damage in dystrophic muscle as compared to unaffected
controls, monitor worsening of muscle pathology in muscular dystrophy, and assess
regression of pathology following therapeutic intervention in muscular dystrophies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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